1. Technical Field
The present invention relates generally to anti-IL-1β antibodies, compositions and methods of using same. The invention is more specifically related to anti-IL-1β antibodies and their manufacture and use. Such antibodies are useful, for example, in methods for treating any of a variety of inflammatory diseases.
2. Description of the Related Art
The IL-1 gene family comprises the agonist cytokines, IL-1α and IL-1β, the natural IL-1 receptor antagonist (IL-1 Ra), and a number of different proteins that directly regulate IL-1 activity. Both IL-1α and IL-1β are synthesized as cytoplasmic precursors. Although IL-1α remains inside the cell, IL-1β is efficiently processed and secreted, making it an attractive target for therapeutic antibodies.
IL-1β is a cytokine produced primarily by monocytes/macrophages following stimulation by bacterial products and immune complexes. In addition, IL-1β is an important mediator of the inflammatory response, and is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis by signaling through NF-κB and c-Jun pathways. IL-1β activates the release of proinflammatory cytokines such as TNF and IL-6, and induces a Th17 bias in the cellular adaptive responses. Excess release of IL-1β has been implicated in autoimmune and inflammatory syndromes characterized by attacks of sterile inflammation of joints, serositis, fever, and skin lesions.
A. IL-1β and Rheumatoid Arthritis (RA)
RA is a chronic inflammatory disease of the joints that is associated with destruction of cartilage and bone. In addition to its local destructive nature, it also can have a pronounced systemic inflammatory component, presenting as fever, headache and fatigue, and may even affect other organs such as the skin, liver, spleen and lymph nodes.
IL-1β is a proinflammatory cytokine acting during the autoimmune process. The contribution made by proinflammatory cytokines such as tumour necrosis factor (TNF)-α and IL-1 has been validated in preclinical animal models and in human RA patients (Dinarello 2002). IL-1β plays a key role in driving joint inflammation and destruction in RA. For example, in RA patients, IL-1β is overexpressed in inflamed synovial tissue, particularly in the lining layer and in sublining cells. IL-1β expression is elevated in draining lymph nodes from affected joints (Dayer 2003). In addition, cartilage from RA patients exhibits upregulation of IL-1β mRNA as compared with normal cartilage. Furthermore, an increased level of IL-1β in synovial fluid has been found to correlate with histological features of RA. Further still, treatment with IL-1Ra (Anakinra, Amgen) improved pathological changes in RA joints (Cunnane 2001) and delayed the progression of joint damage (Bresnihan 2003). This product was approved for treating patients with moderate to severe rheumatoid arthritis who have inadequate responses to conventional disease-modifying antirheumatic drug (DMARD) therapy. An antibody against IL-1β (Canakinumab, Novatis) administrated to methotrexate refractory patients resulted in clinical improvement in ACR20 scores.
B. IL-1β and Diabetes
Type 1 diabetes mellitus is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing β cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose. IL-1β is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. For example, IL-1β inhibits β cell function and promotes Fas-triggered apoptosis of β cells by activating transcription factor NF-κB (Pickersgill 2009).
Type 2 diabetes mellitus is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Chronic elevation of blood glucose (hyperglycemia) induces pancreatic β cell apoptosis by upregulation of Fas (Maedler 2001). This further impairs β cell function, leading to glucotoxicity (Marshak 1999). IL-1β has been implicated in the pathogenesis of type II diabetes. For example, high glucose levels resulted in increased production and release of IL-1β, leading to NF-κB activation, Fas upregulation, DNA fragmentation, and impaired β cell function. (Maedler 2002). IL-1Ra (Anakinra, Amgen) treatment has been shown to prevent hyperglycemia by improving glucose tolerance and insulin secretion in the diet-induced obesity model of Type 2 diabetes (Sauter 2008).
C. IL-1β and Gout
Gout is caused by abnormal purine metabolism and is associated with deposition of mono sodium urate (MSU) crystals in joints and peri articular tissues. Similarly, pseudogout arises from deposition of calcium pyrophosphate dehydrate crystals, owing to unknown causes. Supporting evidence of IL-1β involvement of Gout includes, for example, MSU and calcium pyrophosphate dihydrate crystals activated the NALP3 inflammasome, which causes the production of active IL-1β (Martinon 2006). In addition, blocking IL-1β reduced MSU-crystal-induced inflammation in a mouse model. Further, gout patients who failed to respond to standard anti-inflammatory therapies respond well to the treatment with 100 mg/day of Anakinra. Finally, antibody against IL-1β provides superior pain relief with a more rapid onset compared with triamcinolone acetonide for acute flares in patients with gouty arthritis that are refractory to nonsteroidal anti-inflammatory drugs (So 2007).
D. IL-1β and Cryopyrin-Associated Periodic Syndrome (CAPS)
CAPS comprises a spectrum of apparently distinct, rare, inherited inflammatory disorders of increasing severity, including the familial cold autoinflammatory syndrome, the Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disorder. The majority of these disorders, caused by missense mutations in the NACHT domain of the NALP3/CIAS1 gene, are prime examples of dysregulated processing and secretion of IL-1β.
Despite the known involvement of IL-1β in these and other disease conditions, there remains an important need for more potent humanized monoclonal antibodies that neutralize IL-1β activities and inhibits IL-1β downstream signaling, thereby preventing IL-1β-associated cytokine production and inflammatory diseases. The present invention addresses these needs and offers other related advantages.